Important progress has been made in the treatment of patients with multiple myeloma (MM). Randomized trials of autologous stem cell transplant (ASCT) v. conventional therapy alone have demonstrated significant improvements in survival. Novel drug combinations of thalidomide, lenalidomide and bortezomib plus ASCT have further improved progression-free survival compared older induction regimens. Nevertheless few patients with MM survive without disease progression beyond 10 years. Strategies such as double ASCT, maintenance therapy after ASCT or an allogeneic transplant after ASCT are being studied as ways to improve outcomes. Allogeneic stem cell transplant (allo SCT) provides a tumor-free graft and an immunologic, graft-versus- myeloma effect. Myeloablative allo SCT for MM is associated with a 15-30% probability of disease free survival extending beyond 10 years, the best evidence for cure. Myeloablative allo SCT is, however, historically associated with high transplant related mortality (TRM) of 30-50%. Less intensive, nonmyeloablative allo SCT has been adopted which can reduce mortality to 15-20%, but to be successful, this approach requires that patients with MM receive cytoreductive therapy usually with ASCT, prior to the allo SCT. Even after a tandem auto-allo SCT, however, relapses remain the principal cause of treatment failure. Thus, there is a critical need for improved ways to provide better eradication of residual myeloma cells in the bone marrow. We have shown that 131I-anti-CD45 (BC8) Ab can deliver at least 2-3-fold more radiation to marrow, spleen and sites of leukemia than to any normal organ. We have further shown that high-dose 131I-BC8 Ab can be safely combined with a non-myeloablative regimen in older patients with myeloid malignancies. While CD45 is not widely expressed on the tumor cells of patients with MM, the broad expression of CD45 on all other leukocytes will allow effective targeting to marrow, the principal disease site in MM. Although 131I has been highly successful with regard to delivering targeted radiotherapy, concerns about safety and the transportability of this technology due to high gamma emissions of 131I and the relatively low ss energy of 131I have prompted a shift in strategy to the use of a 90Y-BC8 Ab conjugate for trials in multiple myeloma. 90Y with its lack of gamma emissions, higher ss energy and natural affinity for bone, should be a better isotope for targeting marrow. We will perform dosimetry testing with 111In-BC8 Ab, to establish that more CD45 is targeted to marrow than non-target tissues such as liver, lung and kidneys. Patients will next receive an ablative dose of 90Y-BC8, followed by a period for isotope decay, then the administration of fludarabine 90 mg/m2, external TBI 200 cGY and allo SCT from an HLA matched sibling or unrelated donor. The treatment protocol will involve a 2-stage dose escalation of isotope in patients designed to determine the maximum tolerated dose of 90Y anti-CD45, when combined with fludarabine and TBI in patients with MM receiving allo SCT. Adding marrow targeted radiation to a nonmyeloablative allo-SCT regimen should increase remissions and improve survival.